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Continuous-Flow C(sp3)–H Functionaliza- tions of Volatile Alkanes Using Decatung state Photocatalysis Highlighted article by G. Laudadio, Y. Deng, K. van der Wal, D. Ravelli, M. Nuño, M. Fagnoni, D. Guthrie, Y. Sun, T. Noël This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

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When I opened the window this morning I saw an In this issue amazingly bright and blue sky, it could not be any better. Then I suddenly remembered that a few hours Name Reaction Bio Johann Wilhelm Friedrich Adolf von Baeyer (1835–1917) earlier a new President and Vice-President of the and Victor Villiger (1868–1934): Peracid Oxidation of United States of America had been announced, and I Ketones ...... A173 realized that – for the first time this year – there was Literature Coverage light at the end of the tunnel. This editorial is not Continuous-Flow C(sp3)–H Functionalizations of Volatile about politics, but I believe that the world is a much Alkanes Using Decatungstate Photocatalysis...... A179 better place now: better for science, better for the Literature Coverage Total Synthesis of (+)-Caldaphnidine J ...... A183 environment, better for us and – most of all – better for our children. This is going to be a very strange and Young Career Focus Young Career Focus: Professor Denis Chusov different Christmas for many, but it is a Christmas of (Nesmeyanov Institute, Russian Federation)...... A186 hope, as there are signs that better times are ahead Coming soon ...... A191 of us. But let’s have a look at the last SYNFORM issue of 2020 – a year that will not be missed. We start with a new, extraordinary Name Reaction Bio article by David Lewis on the Baeyer–Villiger reaction, followed Contact by Timothy Noël’s (The Netherlands) Science paper on If you have any questions or wish to send the C(sp 3)–H functionalizations of light hydrocarbons. feedback, please write to Matteo Zanda at: The third article is another Literature Coverage piece: [email protected] it covers the elegant total synthesis of the Daphni- phyllum alkaloid (+)-caldaphnidine by Jing Xu (P. R. of China). The article that closes the issue and the year for SYNFORM is a Young Career Focus interview with Denis Chusov (Russian Federation): look at the picture – besides reading the interesting article – because I think it beautifully represents the sense of hope for the This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. future. Goodbye 2020…

Enjoy your reading!

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Johann Wilhelm Friedrich Adolf von Baeyer (1835–1917) and Victor Villiger (1868–1934): Peracid Oxidation of Ketones

The reaction between ketones and peracids, now known delberg, where Robert Bunsen (1811–1899) was one of the as the Baeyer–Villiger reaction, was first reported by Adolf most important chemists in Germany working in one of the von Baeyer (1835–1917) and his student and collabora- most modern laboratories. While with Bunsen, he published tor, Victor Villiger (1868–1934) in 1899.1 Of the two men, two papers, one on idiochemical induction,5 and a second on von Baeyer is by far the better known, having won the Nobel methyl chloride.6 Prize in Chemistry in 1905. In 1840, Bunsen had begun research on cacodyl compounds,7 and Baeyer continued that research in Bunsen’s laboratory. However, the relationship between student and mentor deteriorated, and an argument between the two men led to Baeyer leaving Bunsen’s research group and joining that of August Kekulé (1829–1896). The two men became life-long friends.

von Baeyer (left) and Villiger (right). Image of von Baeyer courtesy of Science History Institute. The image of Villiger ©2019, Matthew A. Bergs; all rights reserved. Reproduced by permission of the artist.

Johann Friedrich Wilhelm von Baeyer2 was born to Lieutenant-General Jakob Baeyer and Eugenie, née Hitzig, on Bunsen (left) and Kekulé (right). Image of Bunsen courtesy of October 31, 1835. From a young age, he demonstrated his in- Universitätsbibliothek Heidelberg. Public domain image of Kekulé terest in science by his exploration of chemistry. When just downloaded June 2020 from https://commons.wikimedia.org/ wiki/File:Frkekulé.jpg. 9 years old, he was conducting plant nutrition experiments, and just three years later3 he isolated a new double salt of cop- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. per, whose formula was established as CuCO3•Na2CO3•3H2O by Despite his break with Bunsen, Baeyer continued his re- 4 Struve in 1851. search on organic arsenic compounds of the cacodyl (Me2As) At age 17, Baeyer entered the University of Berlin, where series.8 In 1858, he submitted his work on cacodylic acid, he began his study of physics and mathematics. In his two Me2As(O)OH, done in Kekulé’s laboratory, to Berlin University, years there, however, neither physics nor mathematics excited where he was awarded his Ph.D. in 1858. This dissertation9 him as much as chemistry. Both physics and chemistry were was written in Latin. During this time, Kekulé had become taught as complete sciences, looking backwards. Chemistry, Professor at Ghent, and as soon as he held the Ph.D., Baeyer on the other hand, was taught as a new, vibrant science, and it followed him there. was this that changed Baeyer’s mind. In 1860, Baeyer presented his habilitation lecture (again, In 1855, Baeyer left the University for a year of military in Latin), then returned to Berlin as a Privatdozent in the service, and after he had satisfied his obligation he returned Berlin Gewerbeinstitut (The Royal Trade Institute, later the to his studies, this time in chemistry at the University of Hei- Königliche Technische Hochschule Charlottenburg). There he

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began his work with coloring matters, including indigo and alizarin, the red dye from madder root. In 1871, the Alsace– Lorraine region was ceded to France as a result of Prussia’s victory in the Franco–Prussian War of 1870–1871. This event was accompanied by the University of Strasbourg becoming the Kaiser-Wilhem-Universität, and an influx of new, young German-speaking staff members. One of these was 36-year- old Adolf von Baeyer, who became Professor in 1871. Four years later, Baeyer became the successor to Justus von Liebig at the University of Munich, where he spent the rest of his career. Baeyer’s research made a huge impact on the field of organic chemistry. His major contributions to organic chemistry include the Baeyer strain theory (Figure 1),10 and a series of papers on indoles, indoxyl, and isatin,11 culminating in the synthesis of indigo (1; Scheme 1).12

Scheme 2

Figure 1 Baeyer’s strain theory (image taken from Ber. Dtsch. Chem. Ges. 1885, 18, 2269–2281)

Scheme 1

In his degradation studies of uric acid (3), he obtained This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. the dimeric pyrimidinetrione, hydriluric acid (4), as well as monomeric pyrimidinetrione derivatives 5 (violuric acid), 6 (alloxan), and 7 (barbituric acid (Scheme 2), along with Scheme 3 several other pyrimidine derivatives.13 In 1871, he reported the discovery and synthesis of the phthalein dyes (Scheme 3);14 in 1900, he published a paper that proposed a system of proposed that the stability of carbocyclic compounds was de- nomenclature for polycyclic and spirocyclic compounds.15 pendent on the angles’ deviation from the commonly accepted Later he brought his chemical knowledge to the Univer- 109° standard. In 1905, he received the Nobel Prize in Chem sity of Munich, where the true synthesis of indigo developed istry, further distinguishing himself in his field. alongside some of his other projects, such as his work with The other member of the team was Swiss chemist Victor acetylene and polyacetylene which later developed into the Villiger (1868–1934), the son of a lawyer and later City Ad- Baeyer strains theory of carbon rings. More specifically, he ministrator of Lenzburg, and grandson of the Swiss Aarau po-

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litician and reformer, Augustin Kweller (1805–1883). He was Baeyer was very much impressed by the young Villiger, born in the small village of Cham am Zuger See and educated and therefore retained him as an assistant for another eleven at the Aarau Canton School. In 1888, he entered the University years after his graduation. Initially, Villiger worked with of Geneva, where he studied chemistry for a year and a half Baeyer on the ‘hot topic’ at the time – the structure of terpen under Carl Graebe (1841–1927) before completing his com- oid compounds.18 During this work, the β-lactam 14 and pulsory year of military service. stereoisomeric lactones 16 and 17 from camphoronic acid (15) were prepared.19 Literature searches using any search engine and the names Baeyer or Villiger, separately, return more hits on the Baeyer– Villiger reaction than on anything else. This important reaction was first described in the last two years of the nineteenth century,1 and has remained an important synthetic organic

Carl Graebe ca. 1860 (left) and Heinrich Caro ca. 1900 (right). Public domain images retrieved from https://commons.wikimedia.org/wiki/File:Carl_Graebe_1860-07-13.jpg (accessed July 10, 2020) and https://commons.wikimedia.org/wiki/File:Heinrich_ Caro_ca1900.jpg (accessed July 10, 220).

After completing his military service, Villiger volunteered Scheme 4 for several months in the laboratory of the Research Chemist of the City of Zürich. Then, in the spring of 1890, he moved to Munich, where he entered Baeyer’s laboratory. He began his Ph.D. studies there in 1893, focusing on the structure of the benzenoid and hydrobenzenoid compounds that had led to Baeyer’s 1888 paper16 on the structure of benzene, where he had first reported his centric formulas (Figure 2). Villiger received his Ph.D. in 1893 for his studies on hexahydroiso phthalic acid.17 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Figure 2 Baeyer’s centric formulas for the structures of (l–r) hydroquinone, phloroglucinol and terephthalic acid (images taken from Justus Liebigs Ann. Chem. 1888, 245, 103–190) Scheme 5

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method.20 The first examples of the Baeyer–Villiger oxidation of these two ketones with perbenzoic acid in chloroform gave of cyclic ketones were carried out using menthone (18), tetra the diastereoisomeric acetates 33 and 34, showing clearly that hydrocarvone (20), and camphor (22); they are collected in the rearrangement had occurred with retention of configura- Scheme 5. tion. The first reagent used in the reaction was Caro’s acid (monopersulfuric acid), developed by the pioneering dye chemist, Heinrich Caro (1834–1910), who had worked with Baeyer on the synthesis of indole.21

Figure 3 The migratory aptitudes, in the Baeyer–Villiger oxidation, of groups attached to the carbonyl carbon

Scheme 6

Figure 4 The relative reactivities of peracids in the Baeyer– Three distinct mechanisms for the reaction were proposed Villiger reaction (Scheme 6). The first, by Baeyer and Villiger themselves,1a passes through a dioxirane (25), the second, proposed by Wittig and Pieper,22 passes through a carbonyl oxide (26), and the third, proposed by Criegee,23 involves an α-hydroxyalkyl perester (the Criegee intermediate, 27). Evidence confirming the Criegee mechanism was obtained by Doering and Dorfman,24 who used 18O-labeled benzo phenone (marked in red in Scheme 6) as the substrate for the reaction. The carbonyl-18O-labeled ester (29) was obtained as the exclusive product, which is consistent with the Criegee This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. mechanism, but neither of the others. A series of studies25 established the migratory aptitudes of alkyl substituents as shown in Figure 3. The relative reactivities of commonly used peracids are summarized in Figure 4. The Baeyer–Villiger oxidation of C-20 steroidal ketones Scheme 7 was shown quite early on to give a single diastereoisomer of the product;26 shortly thereafter, the rearrangement was shown to occur with retention of configuration.27 This was The Baeyer–Villiger reaction has been a valuable synthetic effected by Turner as shown in Scheme 7. Thus, catalytic hy- method for nearly a century and a quarter, and it should come drogenation of 1-acetyl-2-methylcyclohexene (30) gave cis- as no surprise that the reaction has come under intense re- 1-acetyl-2-methylcyclohexane (31); this ketone was readily search directed at ‘greening’ the reaction.28 Under the stand epimerized by base to the trans isomer (32). The treatment ard conditions, the reaction poses several problems that need

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to be addressed if it is to be carried out under green conditions: 1) Organic peracids are shock-sensitive, and oxidation hazards, covered by special regulations in their transportation and disposal. 2) The stoichiometric reaction generates one mole of the carboxylic acid per mole of peracid; this must be recycled or disposed of as hazardous waste. 3) The reaction involves the use of solvents that are not generally environ- mentally benign. To address these problems, considerable effort has gone into identifying catalytic methods for the reaction. These include the catalytic generation of the peracid from alde hydes and molecular oxygen, a reaction known under the general name of the Mukaiyama oxidation (Scheme 8).29a The Scheme 9 Coupled catalytic alcohol oxidation and Mukaiya- Mukaiyama oxidation was quickly expanded by the use of ma oxidation with oxygen as the terminal oxidant catalysts29b–d and forms the basis for an industrial synthesis of ε-caprolactone (Scheme 8),30a which was still under investiga- tion nearly two decades later.30b over 460 hits). The enzyme structure and sequence have both been determined, and the enzyme has become a popular target for modification.33 Several reviews34 of the uses of these enzymes for asymmetric Baeyer–Villiger oxidations have been published since 2011.

REFERENCES Scheme 8 The Mukaiyama oxidation of cyclohexanone to ε-caprolactone (1) (a) A. Baeyer, V. Villiger Ber. Dtsch. Chem. Ges. 1899, 32, 3625–3633. (b) A. Baeyer, V. Villiger Ber. Dtsch. Chem. Ges. 1900, 33, 124–126. (c) A. Baeyer, V. Villiger Ber. Dtsch. Chem. Hydrogen peroxide also remains one of the most favored Ges. 1900, 33, 858–864. terminal oxidants for the greening of the Baeyer–Villiger oxid (2) For biographies of Baeyer, see: (a) R. Huisgen ation. A search of Google Scholar for 2020 using the keywords Angew. Chem., Int. Ed. Engl. 1986, 25, 297–311. ‘Baeyer–Villiger’ and ‘hydrogen peroxide’ returned 303 results (b) A. de Meijere Angew. Chem. Int. Ed. 2005, 44, 7836–7840. as of October 20. One recent report31 details the in situ ge- (c) G. Nagendrappa Resonance 2014, 19, 489–522. neration of hydrogen peroxide and coupled Baeyer–Villiger (3) W. H. Perkin J. Chem. Soc., Trans. 1923, 123, 1520–1546. oxidation in the presence of molecular oxygen under catal (4) Abstract (Referate) Ann. Chem. Pharm. 1851, 80, 253–255. ysis by cerium(IV) ammonium nitrate and N-hydroxypyridine (5) A. Baeyer Ann. Chem. Pharm. 1857, 103, 178–181. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. (Scheme 9). (6) A. Baeyer Ann. Chem. Pharm. 1857, 103, 181–184. Other researchers have studied methods for reducing the (7) (a) R. Bunsen Ann. Chem. Pharm. 1839, 31, 175–180. shock sensitivity of the oxidant. A representative example of (b) R. Bunsen Ann. Chem. Pharm. 1841, 37, 1–57. recent work in this area32 has identified perdecanoic acid as a (c) R. Bunsen Ann. Chem. Pharm. 1842, 42, 14–46. non-toxic, shock-resistant replacement for the more sensitive (d) R. Bunsen Ann. Chem. Pharm. 1843, 46, 1–48. and toxic lower-molecular-weight peracids. (8) A. Baeyer Ann. Chem. Pharm. 1858, 105, 265–276. The most recent research aimed at making the reaction (9) A. Baeyer Inaugural-Dissertation, University of Berlin, enantioselective is being addressed by examining biocatal Germany, 1858. ysis. Baeyer–Villiger monooxygenases (BVMO) are flavopro (10) A. Baeyer Ber. Dtsch. Chem. Ges. 1885, 18, 2269–2281. tein monooxygenases that have been widely exploited for car- (11) For a history of Baeyer’s work that culminated in the rying out the asymmetric Baeyer–Villiger oxidation (a Google synthesis of indigo, see: A. v. Baeyer, In Adolf von Baeyer’s Scholar search, in July 2020, for the period 2016–2020 returns gesammelte Werke, Vol. 1; A. v. Baeyer, V. Villiger,

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V. Hottenroth, R. Hallensleben, Eds.; Friedrich Vieweg u. 21, 5611–5615. (b) M. Uyanik, K. Ishihara ACS Catal. 2013, Sohn: Braunschweig, 1905; XXXVIII–LV. 3, 513–520. (c) C. Jiménez-Sanchidrián, J. R. Ruiz Tetrahedron (12) A. Baeyer, V. Drewson Ber. Dtsch. Chem. Ges. 1882, 15, 2008, 64, 2011–2026. (d) G.-J. ten Brink, I. W. C. E. Arends, 2856–2864. R. A. Sheldon Chem. Rev. 2004, 104, 4105–4124. (13) (a) A. Baeyer Ann. Chem. Pharm. 1863, 127, 199–236. (29) (a) T. Yamada, K. Takahashi, K. Kato, T. Takai, S. Inoki, (b) A. Baeyer Ann. Chem. Pharm. 1864, 130, 129–175. T. Mukaiyama Chem. Lett. 1991, 20, 641–644. (b) S.-I. Mura- (14) (a) A. Baeyer Ber. Dtsch. Chem. Ges. 1871, 4, 555–558. hashi, Y. Oda, T. Naota Tetrahedron Lett. 1992, 33, 7557–7560. (b) A. Baeyer Ber. Dtsch. Chem. Ges. 1871, 4, 658–665. (c) M. Hamamoto, K. Nakayama, Y. Nishiyama,Y. Ishii (c) A. Baeyer Polytech. J. 1871, 201, 358–362. J. Org. Chem. 1993, 58, 6421–6425. (d) K. Kaneda, S. Ueno, (15) A. Baeyer Ber. Dtsch. Chem. Ges. 1900, 33, 3771–3775. T. Imanaka, E. Shimotsuma, Y. Nishiyama, Y. Ishii J. Org. Chem. (16) A. Baeyer Justus Liebigs Ann. Chem. 1888, 245, 103–190. 1994, 59, 2915–2917. (17) (a) V. Villiger Inaugural-Dissertation, University of Mu- (30) (a) H. A. Wittcoff, B. G. Reuben Industrial Organic Chemi- nich: Germany, 1893. (b) A. Baeyer, V. Villiger Justus Liebigs cals; John Wiley & Sons: New York, 1996; 254. (b) J. Zang, Ann. Chem. 1893, 276, 255–265. Y. Ding, Y. Pei, J. Liu, R. Lin, L. Yan, T. Liu, Y. Lu React. Kinet. (18) (a) A. Baeyer, V. Villiger Ber. Dtsch. Chem. Ges. 1896, 29, Mech. Catal. 2014, 112, 159–171. 1923–1929. (b) A. Baeyer, V. Villiger Ber. Dtsch. Chem. Ges. (31) R. Du, H. Yuan, C. Zhao, Y. Wang, J. Yao, H. Li Mol. Catal. 1898, 31, 2067–2079. (c) A. Baeyer, V. Villiger Ber. Dtsch. 2020, 490, 110947. Chem. Ges. 1899, 32, 2429–2447. (32) M. Sitko, A. Szelwicka, A. Wojewódka, A. Skwarek, (19) A. Baeyer, V. Villiger Ber. Dtsch. Chem. Ges. 1897, 30, D. Tadasiewicz, L. Schimmelpfennig, K. Dziuba, M. Morawiec- 1954–1958. Witczak, A. Chrobok RSC Adv. 2019, 9, 30012–30018. (20) (a) C. H. Hassall Org. React. 1957, 9, 73–106. (b) P. A. S. (33) For a recent example, see: R. D. Ceccoli, D. A. Bianchi, Smith, In Molecular Rearrangements, Vol. 1; P. DeMayo, Ed.; M. A. Carabajal, D. V. Rial Mol. Catal. 2020, 486, 110875. Interscience Publishers, Inc.: New York, 1963; 577–591. (34) (a) H. Leisch, K. Morley, P. C. K. Lau Chem. Rev. 2011, 111, (c) J. B. Lee, B. C. UffQ. Rev. Chem. Soc. 1967, 21, 429–457. 4165–4222. (b) R. Wohlgemuth Comprehensive Organic Syn- (d) G. R. Krow Comprehensive Organic Synthesis 1991, 7, thesis II 2014, 7, 121–144. (c) M. J. L. J. Fürst, A. Gran-Scheuch, 671–688. (e) G. R. Krow Org. React. 1993, 43, 251–798. F. S. Aalbers, M. W. Fraaije ACS Catal. 2019, 9, 11207–11241. (f) M. Renz, B. Meunier Eur. J. Org. Chem. 1999, 737–750. (d) E. Romero, J. R. G. Castellanos, G. Gadda, M. W. Fraaije, (21) (a) A. Baeyer, H. Caro Ber. Dtsch. Chem. Ges. 1877, 10, A. Mattevi Chem. Rev. 2018, 118, 1742–1769. 692–693. (b) A. Baeyer, H. Caro Ber. Dtsch. Chem. Ges. 1877, 10, 1262–1265. (22) G. Wittig, G. Pieper Chem. Ber. 1940, 73, 295–297. (23) R. Criegee Justus Liebigs Ann. Chem. 1948, 560, 127–135. (24) W. v. E. Doering, E. Dorfman J. Am. Chem. Soc. 1953, 75, 5595–5598. (25) (a) S. L. Friess J. Am. Chem. Soc. 1949, 71, 14–15. (b) W. v. E. Doering, L. Speers J. Am. Chem. Soc. 1950, 72, 5515–5518. (c) S. L. Friess, N. Farnham J. Am. Chem. Soc. 1950, 72, This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 5518–5521. (d) S. L. Friess, A. H. Soloway J. Am. Chem. Soc. 1951, 73, 3968–3972. (e) R. R. Sauers, R. W. Ubersax J. Org. Chem. 1965, 30, 3939–3941. (26) (a) R. E. Marker J. Am. Chem. Soc. 1940, 62, 2543–2547. (b) V. Burckhardt, T. Reichstein Helv. Chim. Acta 1942, 25, 821–832. (c) V. Burckhardt, T. Reichstein Helv. Chim. Acta 1942, 25, 1434–1443. (d) L. H. Sarett J. Am. Chem. Soc. 1947, 69, 2899–2901. (27) (a) R. B. Turner J. Am. Chem. Soc. 1950, 72, 878–882. (b) T. F. Gallagher, T. H. Kritchevsky J. Am. Chem. Soc. 1950, 72, 882–885. (28) (a) Y. Zhou, X. Chen, X. Ling, W. Rao Green Chem. 2019,

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Continuous-Flow C(sp3)–H Functionalizations of Volatile Alkanes Using Decatungstate Photocatalysis

Science 2020, 369, 92–96

C(sp3)–H functionalization of alkanes in the absence of proxi- key in our reaction design: not only to make sure that the re- mal directing groups is considered one of the most challenging action medium is well irradiated, but also to bring the gasses and important reactions in contemporary synthetic organic into close contact with the photocatalyst3 (Figure 1).” chemistry. In particular, the incorporation of light alkanes, Preliminary trapping experiments with TEMPO afforded such as methane, ethane, propane and butane, into organic the corresponding TEMPO-propane adducts and gave the group molecules is extremely attractive because it would move the confidence for potentially interesting and useful reactivity. In perception of these chemicals essentially as fuel materials to particular, the authors were intrigued by the excellent selectivi- potentially valuable synthetic building blocks.1 ty provided by decatungstate for the most substituted carbon of Building on their experience in decatungstate-photoca- propane (86:14 ratio of secondary vs primary derivative). talyzed C–H oxidations,2 the group of Prof. Dr. Timothy Noël Prof. Dr. Noël recalls that he immediately realized the im- at the Eindhoven University of Technology (The Netherlands) portance of this seminal result, knowing how difficult it is focused their attention on this valuable – yet absent in organic to obtain good selectivity without the presence of directing synthesis – chemical conversion of gaseous alkanes, which groups. He said: “I still remember the meeting when this re- could benefit from continuous-flow microreactor technology. sult was presented; I became really excited. We decided to in- First author of the paper, Dr. Gabriele Laudadio, remarked: vestigate further to see if we could obtain more synthetically “At the onset of the project, we wondered if we could engage useful results.” At that point, Prof. Dr. Noël asked Yuchao Deng, these inert and insoluble gasses into synthetically valuable who was a visiting Chinese PhD student in the lab, to join the transformations using cheap decatungstate as a photocatalyst. team. Decatungstate had shown its value for activating larger alkane Yuchao and Gabriele carried out the propane optimization scaffolds, often with remarkably high selectivity which can and identified the substrate scope. Gabriele remarked: “The be ascribed to the large size of the catalyst and its electronic decision to employ a Vapourtec setup was crucial, because we properties. If successful, this catalyst would show significant could move from stop flow to continuous flow, accelerating scope, allowing for a diverse set of synthetic applications using our reaction dramatically (Scheme 1). Importantly, a high- Hydrogen Atom Transfer (HAT) photocatalysis.” Furthermore, intensity light source was needed to provide much-reduced as noted by Prof. Dr. Timothy Noël: “Flow chemistry would be reaction times.” This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Figure 1 Decatungstate photocatalysis in flow enables the activation of light alkanes

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Scheme 1 Importance of photon flux and catalyst loading for the effectiveness of the decatungstate C(sp3)–H functionalization of propane

Next, Gabriele and Yuchao set out to explore different “We did not expect this outcome, because activation of C–H gaseous substrates (Scheme 2). Yuchao said: “Activation of bonds on acetonitrile should be prevented due to a polarity isobutane led to a novel methodology to install tert-butyl mismatch,” observed Gabriele, continuing: “We realized that groups in a very easy and scalable way, with high selectivi- this solvent effect could only be observed when the reactivity ty (96:4 tert-butyl versus isobutyl). Also, activation of ethane of tetrabutylammonium decatungstate (TBADT) is pushed to was successfully achieved just by cranking up the pressure, its limits.” which was needed to get ethane into solution, and requiring The presence of this byproduct was suppressed simply by only minor adjustments to the reaction protocol.” using acetonitrile-d3 as solvent. “In this way the correspon- When the ethane transformation was also wrapped up, ding methylated products could be isolated,” confirmed Prof. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. the group was ready to take on the final challenge of methane. Dr. Noël, who concluded: “This method represents an impor- “Methane possesses the strongest C(sp3)–H bonds known in tant strategy to convert light alkanes into value-added mole- Nature and we were not sure whether decatungstate would cules. Via decatungstate photocatalysis, we could break strong be able to cleave those efficiently,” said Prof. Dr. Noël. He con- C(sp3)–H bonds at room temperature, avoiding harsh reaction tinued: “Methane has been a daunting challenge for many de- conditions. In addition, it is important to notice that similar cades, occupying many researchers without much success so transformations typically require organometallic reagents to far. Typically, cleaving methane’s C(sp3)–H bonds requires ex- yield these compounds. Hence, decatungstate photocatalysis tremely high temperatures (> 500 °C) and is only industrially literally allowed us to take the clutter out of synthesis. Our done for a few processes. We reckoned that if methane would laboratory is already working on scaling up this process and work, it would be a big deal.” However, in their first attempts, improving some minor limitations of our method (e.g. deute- the group realized that HAT on acetonitrile was prominent, rated solvents for methane functionalization).” with only traces of the desired methylated product observed.

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Scheme 2 Selection of the scope obtained with the decatungstate C(sp3)–H functionalization of light hydrocarbons. Standard conditions for the decatungstate C(sp3)–H functionalization of isobutane: olefin (1 equiv, 0.1 M), isobutane (4.3 equiv), TBADT (1.0 mol%), CH3CN/H2O (7:1), 10 bar pressure, 60 W of 365 nm LEDs, 4 h reaction time, room temperature. Reported selectivity reflects the tert-butyl/isobutyl ratio. Standard conditions for the decatungstate C(sp3)–H functionalizations of propane: olefin (1 equiv,

0.1 M), propane (4.1 equiv), TBADT (1.0 mol%), CH3CN/H2O (7:1), 10 bar pressure, 60 W of 365 nm LEDs, 4 h reaction time, room temperature. Reported selectivity reflects the isopropyl/n-propyl ratio. Standard conditions for the decatungstate C(sp3)–H functionalizations of ethane: olefin (1 equiv, 0.1 M), ethane (8 equiv), TBADT (2.0 mol%), CH3CN/H2O (7:1), 25 bar pressure, 60 W of 365 nm LEDs, 8 h reaction time, room temperature. Standard conditions for the decatungstate C(sp3)–H functionalizations of methane: olefin (1 equiv, 0.02 M), methane (20 equiv), TBADT (5.0 mol%), CD3CN/H2O (7:1), 45 bar pressure, 150 W of 365 nm LEDs, 6 h reaction time, room temperature.

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REFERENCES About the authors

(1) J. F. Hartwig, M. A. Larsen ACS Cent. Sci. 2016, 2, 281–292. Gabriele Laudadio was born in (2) G. Laudadio, S. Govaerts, Y. Wang, D. Ravelli, H. F. Koolman, 1991 near Pescara, Italy. In 2016 he M. Fagnoni, S. W. Djuric, T. Noël Angew. Chem. Int. Ed. 2018, received his M.Sc. degree in organic 57, 4078–4082. chemistry at the University of Pisa (3) C. Sambiagio, T. Noël Trends Chem. 2020, 2, 92–106. (Italy). His Master’s thesis was conducted under the supervision of Professor A. Carpita. He recently obtained his Ph.D. in chemistry with Cum Laude at the Eindhoven University of Technology (The Dr. G. Laudadio Netherlands) in the group of Prof. Dr. Timothy Noël. His research in terests focus on novel synthetic methodologies combining continuous-flow microreactor technology with electrochem istry and photochemistry.

Timothy Noël was recently pro moted to Full Professor at the University of Amsterdam (The Netherlands) where he is the Chair of Flow Chemistry. His research interests range from organic chem istry to chemical engineering and encompass more specifically flow chemistry, organic synthesis and synthetic catalytic methodology Prof. Dr. T. Noël development. His work has re ceived several awards, including most recently the VIDI award (2015), the Thieme Chemistry Journals Award (2016), the DECHEMA prize (2017) and the Hoogewerff Jongerenprijs 2019. He is the editor in chief of Journal of Flow Chemistry. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Synform Literature Coverage

Total Synthesis of (+)-Caldaphnidine J

Nat. Commun. 2020, DOI: 10.1038/s41467-020-17350-x

“What makes a natural product attractive to synthetic chem rimine-type (Nat. Commun. 2020, DOI: 10.1038/s41467- ists?” asks Professor Jing Xu from SUSTech, Shenzhen (P. R. of 020-17350-x), daphniglaucin C-type (Org. Lett. 2019, 21, China): “The answer is usually the biological activity, or the 4309–4312) and daphnilactone B-type alkaloids (Chin. J. Org. pharmaceutical potential, or the structural complexity that Chem. 2019, 39, 1079–1084),” said Professor Xu. represents an intriguing synthetic challenge.” It is Professor Since Hirata’s isolation of yuzurimine in 1966, nearly 50 Xu’s opinion that the daphniphyllum alkaloids – isolated from yuzurimine-type alkaloids have been isolated, which account plants of the genus Daphniphyllum – clearly belong to this ca for about one-sixth of all known daphniphyllum alkaloids. tegory of compounds, since there is no doubt that they have “Despite extensive synthetic studies, no total synthesis of any long attracted a lot of attention from the synthetic commu member from this largest subfamily of daphniphyllum alkal nity. “Since the milestone synthetic achievements by Profes oids has been achieved. Caldaphnidine J was isolated by the sor Clayton H. Heathcock three decades ago, the synthesis of Yue group in 2008. It possesses a hexacyclic ring system, six various members of daphniphyllum alkaloids has bloomed in contiguous stereogenic centers, two quaternary centers, and this decade, too,” added Professor Xu, who went on to explain an α,β,γ,δ-unsaturated carboxylic ester. This formidable syn that there are more than 300 daphniphyllum alkaloids known thetic challenge prompted us to initiate a research program to to date, making up a structurally remarkably diversified and ward its synthesis,” explained Professor Xu. He continued: “It fascinating natural product family. As shown in Figure 1, was a long, extremely difficult but finally successful journey. daphniphyllum alkaloids from nine subfamilies have been As depicted in Scheme 1, the highlights of our approach in synthetically accessed so far. “Our group has a research focus clude 1) a facile six- → seven-membered ring expansion stra on the total synthesis of daphniphyllum alkaloids with highly tegy; 2) Shi’s Pd-catalyzed regioselective hydroformylation; 3) diversified structures, including calyciphylline A-type (Angew. a Sm(II)-mediated pinacol coupling; 4) a novel, one-pot Swern Chem. Int. Ed. 2019, 58, 7390–7394), daphnezomine A-type oxidation/ketene dithioacetal Prins reaction; 5) a regioselec (J. Am. Chem. Soc. 2019, 141, 11713–11720), bukittinggine- tive elimination; and 6) a regio- and diastereoselective hydro type (J. Am. Chem. Soc. 2019, 141, 13043–13048), yuzu genation.” The group’s work resulted in the first synthesis of a This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Figure 1 Daphniphyllum alkaloids from nine subfamilies have been synthetically accessed

Synform Literature Coverage

Scheme 1 Total synthesis of (+)-caldaphnidine J

member of the largest subfamily of daphniphyllum alkaloids. Professor Xu remarked: “We believe that the strategies and methods applied in our work should inspire further advances in the synthesis of daphniphyllum alkaloids and much more.” Professor Xu commented that one of the most interesting findings in the group’s approach to the title compound was This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. probably the one-pot Swern oxidation/ketene dithioacetal Prins reaction. “As we mentioned in our manuscript, the oxid ation of the secondary hydroxyl group in compound 6 gave decomposition or messy results under various conditions,” he explained, continuing: “However, the TFAA/DMSO condi tions gave a relatively ‘clean’ reaction that produced a major, yet unknown, product.” He concluded: “To our great pleasure, thorough characterizations of this unknown compound finally disclosed a novel one-pot Swern oxidation/ketene dithioacetal Prins reaction.”

Synform Literature Coverage

About the authors

Lian-Dong Guo obtained his PhD in 2016 from Xiamen University (P. R. of Heyifei Fu obtained his BSc in chem China) under the direction of Profes- istry from SUSTech (P. R. of China) in sor Pei-Qiang Huang. He joined Pro- 2019 under the supervision of Prof. fessor Jing Xu’s group at SUSTech as Jing Xu, where he participated in a postdoctoral researcher from 2016– the total synthesis of daphniphyllum 2020. His research focuses on the alkaloids. He then moved to Dart- total synthesis of natural products, in mouth College (USA) to pursue his particular, the synthesis of alkaloids. PhD studies under the supervision of Prof. Ivan Aprahamian. Dr. L-D Guo H. Fu

Yan Zhang obtained his BS in 2017 from Hebei University of Science and Yuye Chen received his PhD from Technology (P. R. of China), where he University of Macau (Macau, P. R. of carried out undergraduate research China) in 2019, then joined the group under the supervision of Prof. Zhi-Wei of Prof. Jing Xu as a postdoctoral re- Zhang. He obtained his MS degree in searcher at SUSTech (P. R. of China). 2019 under the supervision of Prof. He is currently focusing on the total Jing Xu. Currently, he is a PhD student synthesis of complex natural pro- in the same research group. His re- ducts. search focuses on the total synthesis Y. Zhang of natural products. Dr. Y. Chen

Jingping Hu obtained his BS in 2014 Jing Xu received his BS from Nan- from Anhui University (P. R. of China). chang University (P. R. of China, 2000) In 2014, he moved to Lanzhou Univer- and MS from Tongji University (P. R. of sity (P. R. of China) to complete his MS China, 2004). After that, he joined the degree under the supervision of Prof. Wuxi PharmaTech (now Wuxi AppTec, Ying Li. Currently, he is a PhD student P. R. of China) for one year as a re- at Southern University of Science and search scientist. He received his PhD Technology (SUSTech, P. R. of China) from Leipzig University (Germany) under the supervision of Prof. Jing Xu. in 2009. He then moved to the Uni- His research focuses on the total syn- versity of California, San Diego (USA) J. Hu thesis of natural products. Prof. J. Xu to pursue postdoctoral research. In 2014, he began his independent Chengqing Ning obtained his PhD career at SUSTech (P. R. of China) where he is currently a pro- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. from Central South University (P. R. of fessor. His research interests include natural product synthesis China) in 2015 under the supervision and drug discovery. of Prof. Niefang Yu. He then moved to SUSTech (P. R. of China) as a postdoctoral research fellow in Prof. Jing Xu’s lab, where he is currently a research assistant professor. His research fo cuses on small-molecule medicinal chemistry and natural product syn- Prof. C. Ning thesis.

Synform Young Career Focus

Young Career Focus: Professor Denis Chusov (Nesmeyanov Institute, Russian Federation)

Background and Purpose. SYNFORM regularly meets young up-and-coming researchers who are performing exceptionally well in the arena of organic chemistry and related fields of research, in order to introduce them to the readership. This Young Career Focus presents Professor Denis Chusov (Nesmeyanov Institute, Russian Federation).

Biographical Sketch INTERVIEW

SYNFORM What is the focus of your current research activity?

Prof. D. Chusov The development of highly effective catal ytic systems is equally important for core academic research and industrial applications. However, nowadays the progress is typically achieved by the preparation of more structurally complex and expensive catalysts. The finding of application of simple catalysts for new reactions is one of the goals that we are focused on. Other areas of our research involve the search for new ways of activation of simple catalysts to gain higher activity in known reactions. Currently research in our group focuses on developing new selective reductive addition reac tions.

SYNFORM When did you get interested in synthesis?

Prof. D. Chusov Prof. D. Chusov I believe that mathematics is the first sub ject which requires thinking. I have always been interested in Denis Chusov graduated from the Moscow Chemical Lyceum (Russian Federation) and obtained his undergraduate degree mathematics. Once I went to a municipal mathematics olym from the Higher Chemical College of the Russian Academy of piad and won a prize. After that, I received some invitations Sciences (Russian Federation). He defended his Ph.D. thesis to various mathematics schools. My friend suggested I attend under the supervision of Prof. Yuri N. Belokon at the Nes- evening classes at the Moscow Chemical Lyceum; I went there and decided to enroll at the Lyceum for a full-time study. To meyanov Institute of Organoelement Compounds in Moscow This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. (Russian Federation). He then worked as a visiting researcher do this, I needed to pass the entrance exams and although I at Newcastle University (UK) with Prof. Michael North and at got a good grade in mathematics, I failed the chemistry exam. Universite? Paris-Sud 11 (France) with Prof. Henri Kagan. His Therefore, I needed to study chemistry over the summer to postdoctoral studies were conducted at Max-Planck-Institut pass the exam resit in autumn. fu?r Kohlenforschung (Germany) with Prof. Benjamin List. At the Chemical Lyceum I studied many subjects including He is currently an Associate Professor at the Nesmeyanov mathematics, chemistry, and human sciences. At that time, Institute (Russian Federation). I figured out that I am very interested in organic chemistry. Fortunately, a unique situation was created in the Chemical Lyceum: students were able to carry out research in the real research institutes, so I was given an opportunity to parti- cipate in the work of a research laboratory and carry out a pro ject in organic synthesis when I was only 16 years old.

Synform Young Career Focus

SYNFORM What do you think about the modern role and prospects of organic synthesis?

Prof. D. Chusov Seems like organic chemistry still has a special place amongst the interests of students in chemical universities and schools. In this area the connection between science and art becomes more visible. It is shown in the beauty of certain syntheses, in the elegance of obtaining certain com pounds, in the uniqueness of many reactions. It can be said that in organic synthesis, some kind of design at the smallest size of the objects is possible. Unfortunately, we cannot create Scheme 1 Classical way of reductive amination the desired new objects with a certain consistency at the sub-molecular level. As for the prospect of organic synthesis, it is hard to imagine that in the future, medicinal chemistry or materials science can be developed without an organic or organoelement compound.

Scheme 2 Ideal way of reductive amination SYNFORM Could you tell us more about your group’s areas of research and your aims?

Prof. D. Chusov The main research area of our group focuses on reductive additions without an external hydro gen source. Let’s look at this idea on the example of reductive amination reaction. I like this reaction very much, as the ma Scheme 3 Reductive amination using carbon monoxide as a jority of medicinal chemists do, because it is a very convenient reducing agent method of amine synthesis. It is a reliable method which can be applied to a wide variety of substrates. The starting materials are aldehydes or ketones and ammonia or amines. In industry, As a result, we developed even more than reductive amin aldehydes are easily obtained from hydrocarbons, though even ation protocols without an external hydrogen source (Angew. simple alcohols, like propanol, butanol and other terminal al Chem. Int. Ed. 2014, 53, 5199–5201; Org. Lett. 2015, 17, 173– cohols with higher molecular weight, are obtained from the 175; Org. Biomol. Chem. 2017, 15, 6384–6387). Interaction corresponding aldehydes. On the other hand, aldehydes can be of any carbonyl compound with any hydrogen-containing easily converted into various classes of chemical compounds. nucleophile is in line with this concept (Mendeleev Commun. The classical version of reductive amination involves the 2018, 28, 113–122). We showed that CH-acids and other CH- interaction of an aldehyde with an amine. After that we get a nucleophiles (like ketones with an α-hydrogen atom), amides, Schiff base and water (Scheme 1). Then molecular hydrogen carboxylic acids can be applied in this protocol (Scheme 4). with a catalyst is added to the Schiff base to obtain the target It is interesting that the method appeared to be very selec This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. amine. Precise analysis shows that at the first step we take two tive. Hydrogen and hydride agents can reduce not only vari hydrogen atoms from the molecules, and at the second step ous functional groups in target compounds (Table 1) (ACS Ca- we add them again. That does not look like a very effecient tal. 2016, 6, 2043–2046) but even the starting aldehydes and idea, and it means that we can avoid using an external hydro ketones, which then leads to a complete failure of the reaction gen source. Ideally, we can mix ammonia or an amine with (Synthesis 2019, 51, 2667–2677). a carbonyl compound and get a more substituted amine and Moreover, using CO allowed us to synthesize tertiary ste oxygen (Scheme 2). However, in a reduction process it is not rically hindered amines via reductive amination (Chem. Com- realistic to get an oxidizing agent such as oxygen in the end; mun. 2016, 52, 1397–1400). The classical approach with mo therefore we need a reagent which is able to scavenge the oxy lecular hydrogen does not lead to the target amines since even gen atom and does not contain hydrogen atoms in it. For this reduction of an aromatic ring with hydrogen is easier than ob purpose, we use carbon monoxide, a waste product of steel taining such hindered amines (Scheme 5). Even direct reduc manufacturing (Scheme 3). tive amination of sterically hindered ketones like camphor is

Synform Young Career Focus

Scheme 4 Reductive addition of different hydrogen-containing nucleophiles without an external hydrogen source

However, when we read a scientific article, including the ori ginal article about sodium triacetoxyborohydride, we can see that even there the researchers show that these hydrides do reduce aldehydes. That is the reason I like our approach. It is very convenient since the reaction can be carried out without any solvent at low catalyst loadings if needed, and even at such conditions we can get nothing but the target compound in the reaction This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. mixture at the end. Moreover, if you do not have access to car bon monoxide gas you can replace it with other non-hydrogen Table 1 Functional group tolerance in the reductive amination reaction using different reducing agents non-gaseous reducing agents such as metal carbonyls [e.g. iron carbonyl (Org. Biomol. Chem. 2017, 15, 10164–10166; Eur. J. Org. Chem. 2019, 32–35)]. We used this approach for very challenging using classical reductive agents (Org. Biomol. the total synthesis of different compounds (Scheme 7) J.( Org. Chem. 2017, 15, 10164–10166). Chem. 2020, 85, 9347–9360). For example, we designed the Notably, it is written in organic chemistry textbooks that total synthesis of luotonin A from two simple compounds like for reductive amination reactions, special reducing agents nitrobenzaldehyde and hydroxyproline (Scheme 8). exist. For example, sodium cyanoborohydride and triaceto xyborohydride selectively conduct this reaction since they do not reduce the C=O bond in an initial aldehyde (Scheme 6).

Synform Young Career Focus

85% yield OMe RhCl3 O (2 mol%) + H2NPMP 50 bar N 160 °C, 20 h 0% yield

Side products in the reductive amination using molecular hydrogen: OMe OH

N N H H

Scheme 5 Synthesis of tertiary sterically hindered amines using CO vs. H2

Scheme 6 Advantages vs. challenge of reductive amination with sodium cyanoborohydride and sodium triacetoxyborohydride

Retrosynthetic scheme of luotonin A Scheme 8 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

SYNFORM What is your most important scientific achieve ment to date and why?

Prof. D. Chusov My most significant achievement is that I chose science, and it means that now I do not have a limit in evolution at my work. And my most important scientific achievement in my opinion is the development of reduction Scheme 7 Total synthesis of vasicinone, isaindigotone, luoto- protocols without an external hydrogen source. When we nin, and rutaecarpine based on reductive addition of amines have enough hydrogen atoms in the starting compounds and to nitrobenzaldehydes without an external hydrogen source all we need is to combine these compounds and reduce the

Synform Young Career Focus

resulting molecule, we can use a reducing agent which does not contain hydrogen atoms and obtain the target compounds with tolerance to all the functional groups and even to obtain such compounds which totally could not have been obtained before. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Synform Impressum

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